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  • aromatase inhibitor The present study was the first

    2020-03-24

    The present study was the first to examine how COMT genotype and estradiol are associated with aromatase inhibitor functioning in healthy postmenopausal women. We hypothesized that with decreased circulating estradiol after menopause, the COMT genotype relationship to cognition would remain and perhaps become more exaggerated. Specifically, we hypothesized that working memory-related brain activation would decrease as the hypothesized dopamine level increased. That is, women with a Met/Met genotype would have decreased activation and better performance than women with a Val/Val genotype. To examine how estradiol is related to brain functioning in a similar way to Jacobs and D\'Esposito (2011), we created high and low estradiol groups by doing a median split on the circulating estradiol levels. We hypothesized that the high estradiol group with the Met/Met genotype would perform the best and have least activation compared to the other groups. This group did not perform the best in the Jacobs and D\'Esposito (2011) study because it was suggested that this estradiol/COMT genotype combination represented excess dopamine and less efficient performance. However, after menopause when the overall estradiol levels are lower, those postmenopausal women with higher levels of circulating estradiol and the Met/Met genotype may have an advantage in working memory and related brain functioning.
    Materials and method
    Results
    Discussion We hypothesized that higher levels of dopamine would be beneficial to cognition in postmenopausal women. We operationalized increased levels of dopamine with being Met/Met homozygous for the COMT gene. Women who are homozygous for Met have less transcription of the COMT enzyme than those who are Val homozygotes (Chen et al., 2004, Lachman et al., 1996, Lotta et al., 1995). COMT is also primarily located in the frontal lobes of the brain and is therefore likely to influence frontal lobe dopamine levels (Matsumoto et al., 2003). In addition, we examined levels of estradiol and operationalized higher levels of dopamine with having higher levels of estradiol. There is an estrogen response element on the COMT promotor region (Jiang et al., 2003, Weinshilboum, 2006, Xie et al., 1999). Thus, when estrogen is present, COMT transcription does not occur and there is more dopamine available in the synapse. Our data showed that the hypothesized dopamine level was inversely related to brain activation during the N-back task, which has been interpreted in prior studies as more efficient brain functioning (Jacobs and D\'Esposito, 2011). However, performance on our task was not related to inferred dopamine level. Below we hypothesize about why this data pattern was observed, how it relates to the prior literature, and the contribution it makes to what is known about individual differences in cognition after menopause. Jacobs and D\'Esposito (2011) used COMT genotype and estradiol levels as proxy measures for dopamine in younger normal cycling premenopausal women. Their imaging data showed a linear decrease in the middle frontal gyrus associated with an increase in inferred dopamine across groups with the Met/Met high estradiol group having greatest decreased activation and the Val/Val low estradiol group having the least decrease with the other groups in the middle. For the performance analysis, they examined correct rejection of lures during the N-back task and not an overall accuracy measure like proportion correct or sensitivity. Their results showed that the Met/Met low estradiol group performed best on the lure items and the relationship between dopamine and working memory performance was an inverted U as is often found in the relationship of neurotransmitter levels and cognitive functioning. They emphasized the importance of the COMT genotype in understanding the role of estrogen on cognition in premenopausal women. Overall, the results in the present study from postmenopausal women were similar to the younger premenopausal women with regard to the direction of the brain imaging activation pattern, but the specific region was different and the size of the effect in postmenopausal women appears to be smaller. We did find a dopamine-sensitive decrease in the right precentral gyrus (BA 6). Jacobs and D\'Esposito (2011) found activation in the bilateral MFG. In postmenopausal women, this dopamine-sensitive region was smaller in size, more posterior, and right lateralized. In addition, we also found no effect of COMT and estradiol on working memory accuracy performance as measured by sensitivity, bias, and proportion correct. We did not build lure items into our task so we were not able to examine these responses similar to Jacobs and D\'Esposito (2011). Thus, in the presence of postmenopausal estradiol levels, COMT genotype may be less important for explaining individual differences in cognition compared to premenopausal women. As the fluctuating levels of estradiol during the menstrual cycle cease to occur, estradiol\'s relationship with dopaminergically driven cognition also appears to decline.